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HER2-receptor quantification in breast cancer patients by imaging with ABY-025 Affibody and PET
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

Breast cancer is the most common malignancy in women worldwide. Human epidermal growth factor receptor type 2 (HER2) is overexpressed in up to 20% of breast cancer cases and is considered an important prognostic factor and a therapeutic target. With the introduction of HER2-targeted therapy, it was important to recognize patients who will likely benefit from such treatment. Immunohistochemistry staining performed on a tumor biopsy, with in situ hybridization to detect gene amplification if needed, is the current gold standard method for HER2 receptor quantification. However, in cases with multiple metastases, it is both unfeasible and impractical to perform multiple biopsies without risking higher morbidity. Molecular imaging with tracers specifically targeting HER2 receptors provides a non-invasive approach, which allows full body quantification without the serious side effects associated with invasive biopsies. The molecule of focus in this thesis work is Affibody ZHER2:2891 (ABY-025) molecule that has a high affinity and selectivity towards HER2 receptors.

This thesis is based on four original articles. The first part focused on the aspect of breast cancer imaging using HER2-targeting gallium-labeled tracer 68Ga-ABY-025 in positron emission tomography (PET) and its role in predicting breast cancer outcome. The second part was to investigate the effect of different risk factors on developing brain metastasis, the overall survival and the effect of HER2-targeted treatment on breast cancer brain metastasis based on Uppsala County cancer registry.

We demonstrated that HER2-binding Affibody PET kinetics can be explained using a two-tissue compartment model and SUV values correlated well with the influx rates calculated using kinetic modeling, supporting its use to measure actual HER2 receptor binding. Phase II study demonstrated the potential of 68Ga-ABY-025 PET to predict the treatment outcome more accurately compared to biopsy HER2-status that uses the traditional immunohistochemistry staining and in situ hybridization techniques. 68Ga-ABY-025 PET provided accurate staging and reduced false positive 18F-FDG PET results in HER2-positive cases. HER2-positive molecular subtypes were associated with an increased risk of developing brain metastasis. Yet, longer survival times were observed in HER2-positive subtypes receiving HER2-targeted therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. , p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2004
Keywords [en]
PET, Breast cancer, HER2, Affibody, ABY-025, Molecular imaging, Kinetic modelling, Brain metastasis
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-517674ISBN: 978-91-513-1995-7 (print)OAI: oai:DiVA.org:uu-517674DiVA, id: diva2:1819436
Public defence
2024-02-16, H:son Holmdahlsalen, Dag Hammarskjöldsväg 8, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2024-01-23 Created: 2023-12-14 Last updated: 2024-01-23
List of papers
1. Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
Open this publication in new window or tab >>Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
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2020 (English)In: EJNMMI Research, E-ISSN 2191-219X, Vol. 10, no 1, article id 21Article in journal (Refereed) Published
Abstract [en]

Background: High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with Ga-68-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between Ga-68-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of Ga-68-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.

Methods: Dynamic Ga-68-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K-1) and irreversible binding (K-i) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to K-i.

Results: Characterization of HER2 expression in smaller liver metastases was improved using parametric images. K-i values from parametric images agreed very well with VOI-based gold standard (R-2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with K-i values from both the two-tissue compartment model and Patlak method (R-2 = 0.87 and 0.95, both p < 0.001). Ga-68-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).

Conclusion: Ga-68-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein K-i highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.

Place, publisher, year, edition, pages
SPRINGEROPEN, 2020
Keywords
HER2 receptor, Metastatic breast cancer, Affibody, Dynamic PET, Kinetic modelling
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-408918 (URN)10.1186/s13550-020-0603-9 (DOI)000522034700001 ()32201920 (PubMedID)
Funder
Swedish Cancer SocietyThe Breast Cancer Foundation
Available from: 2020-04-17 Created: 2020-04-17 Last updated: 2023-12-14Bibliographically approved
2. Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.
Open this publication in new window or tab >>Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.
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2023 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 64, no 9, p. 1364-1370Article in journal (Refereed) Published
Abstract [en]

Imaging using the human epidermal growth factor receptor 2 (HER2)-binding tracer 68Ga-labeled ZHER2:2891-Cys-MMA-DOTA ([68Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [68Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [68Ga]Ga-ABY-025 PET/CT, [18F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [18F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [68Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [68Ga]Ga-ABY-025 PET/CT cutoff SUVmax of 6.0 predicted a Δ-TLG lower than -25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67-0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (-71% [95% CI, -58% to -83%]; P < 0.0001) than in MBC (-27% [95% CI, -16% to -38%]; P < 0.0001), but [68Ga]Ga-ABY-025 SUVmax was similar in both with a mean SUVmax of 9.8 (95% CI, 6.3-13.3) and 13.9 (95% CI, 10.5-17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [68Ga]Ga-ABY-025 PET/CT SUVmax (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [68Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [68Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.

Place, publisher, year, edition, pages
Society of Nuclear Medicine, 2023
Keywords
HER2 positive, PET/CT, [68Ga]Ga-ABY-025, affibody molecules, breast cancer
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-514020 (URN)10.2967/jnumed.122.265364 (DOI)001120138300009 ()37442602 (PubMedID)
Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2024-01-08Bibliographically approved
3. 68Ga-ABY-025 PET in HER2-positive breast cancer: assessment of small axillary lesions
Open this publication in new window or tab >>68Ga-ABY-025 PET in HER2-positive breast cancer: assessment of small axillary lesions
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-517671 (URN)
Available from: 2023-12-11 Created: 2023-12-11 Last updated: 2023-12-14
4. Overall survival amongst patients with breast cancer brain metastasis: A cohort study based on Uppsala county cancer registry
Open this publication in new window or tab >>Overall survival amongst patients with breast cancer brain metastasis: A cohort study based on Uppsala county cancer registry
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-517673 (URN)
Available from: 2023-12-11 Created: 2023-12-11 Last updated: 2023-12-14

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